Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin

Liang, Yan; Wang, Yiting; Liu, Jingyang; Nie, Yali; Zhong, Xiao‐bo; Kan, Quancheng; Zhang, Lirong

doi:10.1124/mol.117.108225

Cited by 28 publications

(31 citation statements)

References 43 publications

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“…Differences were considered significant at P , 0.05. p300 on the promoter of the glucose transporter GLUT2 (Ban et al, 2002). Additionally, our recent study reported that rifampicin enhances interactions between pregnane X receptor and NCOA6/p300 in the induction of CYP3A4 (Yan et al, 2017). Similarly, in the present study HNF1A interacted with NCOA6/p300 to activate UGT1A1 expression.…”

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confidence: 74%

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

et al. 2017

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Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression. We further showed that the transcription factor hepatocyte nuclear factor 1 (HNF1A) affects histone modifications around the locus. In particular, we demonstrated that by recruiting HNF1A the cofactors mixed-lineage leukemia 1, the transcriptional coactivator p300, and nuclear receptor coactivator 6 aggregate at the promoter, thereby regulating histone modifications and subsequent UGT1A1 expression. In this study, we proposed new ideas for the developmental regulation of metabolic enzymes via histone modifications, and our findings will potentially contribute to the development of age-specific therapies.

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confidence: 74%

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

et al. 2017

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“…In the present study, we used a chronic treatment with low-dose DEX that mimics the use in humans of rifampicin, which can be administered to cholestatic patients [ 43 ]. This was done because rifampicin and DEX are the prototypical PXR-inducers in humans [ 44 , 45 ], and rodents [ 38 ], respectively. The dose of DEX used in this work was unable to activate neither GR or PXR, while it did unexpectedly activate only CAR.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone counteracts hepatic inflammation and oxidative stress in cholestatic rats via CAR activation

et al. 2018

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Glucocorticoids (GCs) are currently used for the therapeutic management of cholestatic diseases, but their use and molecular mechanism remain controversial. The aims of this study were 1) to assess the therapeutic effect of a 2-week treatment with the GC dexamethasone on hepatic damage in bile duct-ligated rats; 2) to investigate its effect on the activation of the nuclear receptors (NRs) pregnane X receptor (PXR), constitutive androstane receptor (CAR) and GC receptor (GR), and NF-kB, as well as on oxidative stress and bile acid (BA) hepatic composition. Cholestasis was induced by ligation of bile duct (BDL animals) in 16 male Wistar-Kyoto rats, and eight of them were daily treated by oral gavage with 0.125 mg/ml/kg DEX for 14 days. Eight Sham-operated rats were used as controls. Severity of cholestasis was assessed histologically and on plasma biochemical parameters. The nuclear expression of NF-kB (p65), GR, PXR and CAR was measured in hepatic tissue by Western Blot. Oxidative stress was evaluated by measuring malondialdehyde, carbonylated proteins, GHS and ROS content in rat livers. LC-MS was used to measure the plasma and liver concentration of 7 BAs. Histological findings and a significant drop in several markers of inflammation (p65 nuclear translocation, mRNA expressions of TNF-α, IL-1β, IL-6) showed that DEX treatment reversed cholestasis-induced inflammation, and similar results have been obtained with oxidative stress markers. The nuclear expression of p65 and CAR were inversely correlated, with the latter increasing significantly after DEX treatment (p<0.01 vs vehicle). Hepatic BA levels tended to drop in the untreated cholestatic rats, whereas they were similar to those of healthy rats in DEX-treated animals. Plasma BAs decreased significantly in DEX-treated animals with respect to untreated cholestatic rats. In conclusion, DEX reduces inflammation and oxidative stress in BDL rats, and probably CAR is responsible for this effect. Therefore, this NR represents a promising pharmacological target for managing cholestatic and inflammatory liver diseases.

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“…Western Blot Analysis. Total proteins of the liver tissues or treated cells were prepared using a RIPA buffer (150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, and 50 mM Tris, pH 8.0), and protein concentrations were determined using a previously described method Yan et al, 2017). Protein samples were separated by 12% SDS-polyacrylamide gel electrophoresis and transferred to PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

The HNF1α-Regulated LncRNA HNF1α-AS1 Is Involved in the Regulation of Cytochrome P450 Expression in Human Liver Tissues and Huh7 Cells

Wang

Liang

Liu

et al. 2019

J Pharmacol Exp Ther

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Expression of cytochrome P450s (P450s) is regulated by epigenetic factors, such as DNA methylation, histone modifications, and noncoding RNAs through different mechanisms. Among these factors, long noncoding RNAs (lncRNAs) have been shown to play important roles in the regulation of gene expression; however, little is known about the effects of lncRNAs on the regulation of P450 expression. The aim of this study was to explore the role of lncRNAs in the regulation of P450 expression by using human liver tissues and hepatoma Huh7 cells. Through lncRNA microarray analysis and quantitative polymerase chain reaction in human liver tissues, we found that the lncRNA hepatocyte nuclear factor 1 alpha antisense 1 (HNF1a-AS1), an antisense RNA of HNF1a, is positively correlated with the mRNA expression of CYP2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 as well as pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Gain-and loss-of-function studies in Huh7 cells transfected with small interfering RNAs or overexpression plasmids showed that HNF1a not only regulated the expression of HNF1a-AS1 and P450s, but also regulated the expression of CAR, PXR, and aryl hydrocarbon receptor (AhR). In turn, HNF1a-AS1 regulated the expression of PXR and most P450s without affecting the expression of HNF1a, AhR, and CAR. Moreover, the rifampicin-induced expression of P450s was also affected by HNF1a and HNF1a-AS1. In summary, the results of this study suggested that HNF1a-AS1 is involved in the HNF1a-mediated regulation of P450s in the liver at both basal and drug-induced levels.

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Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin

Cited by 28 publications

References 43 publications

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1

Dexamethasone counteracts hepatic inflammation and oxidative stress in cholestatic rats via CAR activation

The HNF1α-Regulated LncRNA HNF1α-AS1 Is Involved in the Regulation of Cytochrome P450 Expression in Human Liver Tissues and Huh7 Cells

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